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Updated: Sep 5, 2025
Tissue Triage and Freezing for Models of Skeletal Muscle Disease
Published on: July 15, 2014
Transcript-Based Diagnosis and Expanded Phenotype of an Intronic Mutation in TPM3 Myopathy
Yuval Yogev1, Jacob Bistritzer2, Yair Sadaka3,4
1The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Introduction:
Congenital myopathies are a broad group of inborn muscle disorders caused by a multitude of genetic factors, often characterized by muscle atrophy and hypotonia.
Methods:
Clinical studies, imaging, histology, whole-exome sequencing (WES) and muscle tissue RNA studies.
Results:
We describe a severe congenital myopathy manifesting at birth with bilateral clubfeet, delayed motor development and hypotonia, becoming evident by 4 months of age. At 3 years of age, the patient had tongue fasciculations, was bedridden, and was chronically ventilated via tracheostomy. Imaging studies demonstrated severe muscle atrophy and, surprisingly, cerebral atrophy; electromyography demonstrated a myasthenic pattern and histological evaluation did not facilitate a definitive diagnosis. Trio WES did not identify a causative variant, except for a non-canonical intronic TPM3 c.118-12G>A variant of uncertain significance. Transcript analysis of muscle tissue from the patient proved the pathogenicity of this homozygous variant, with a 97% reduction in the muscle-specific TPM3.12 transcript.
Discussion:
This study broadens the phenotypic spectrum of recessive TPM3 disease, highlighting tongue fasciculations and bilateral clubfoot, as well as possibly-related cerebral atrophy. It also shows the importance of a broad approach to genetic analysis and the utility of RNA-based studies, demonstrating efficacy of early genome and transcriptome queries in facilitating rapid and cost-effective diagnosis of congenital myopathies.
